Project Abstract Common-disease associated variants systematically localize to the regulatory DNA of specific cell and tissue types, suggesting that the genome-wide activity of regulatory elements can provide key epigenetic context for the interpretation of genetic variation. However, regulatory elements in mammalian genomes are exquisitely sensitive to genomic context and often regulate distant genes. Thus, interpretation of the functional conse- quences of sequence variation at non-coding regulatory elements has been impeded by the lack of a mecha- nistic understanding of genomic regulatory structure and the sequence determinants of long-range interaction. I propose an experimental and computational research plan to address this pressing problem, focusing on four fundamental questions: Do sequence features of distal regulatory elements specify interaction with nearby promoters? To what extent do intervening sequence elements affect long-distance interaction genome-wide? Is long-distance interaction organized into functional domains in mammalian genomes? Do regulatory elements act in modular combinations of reducible activities, or do they instead form constellations of emergent regulato- ry function? This work will dramatically extend our understanding of the genomics of transcriptional regulation, facilitating systems-level analyses of common disease-associated variation in human genomes and industrial applications for genome editing and gene therapy.